Project Grant R21HD106615

CMV DYNAMICS AND TRANSMISSION AMONG PREGNANT WOMEN LIVING WITH HIV - PROJECT SUMMARY CYTOMEGALOVIRUS (CMV) IS THE LEADING CONGENITAL INFECTION GLOBALLY, RESULTING IN AN ENORMOUS BURDEN OF CHILDHOOD HEARING LOSS AND NEURODEVELOPMENTAL DELAY. THE 20 MILLION WOMEN LIVING WITH HIV (WLWH) WORLDWIDE ARE MORE LIKELY TO HAVE ACTIVE CMV REPLICATION THAN WOMEN WITHOUT HIV AND ARE MORE LIKELY TO TRANSMIT CMV TO THE 1.3 MILLION HIV-EXPOSED INFANTS BORN ANNUALLY. COMBINING GENOME-WIDE SEROLOGIC AND VIROLOGIC ANALYSES, THIS PROJECT WILL USE EXISTING SAMPLES TO NEW TOOLS TO CHARACTERIZE CMV REINFECTION AND SHEDDING DURING PREGNANCY. WE WILL ALSO EXPLORE THE ROLE OF SPECIFIC GENOTYPES AMONG STRAINS CAUSING MATERNAL REINFECTION AND CONGENITAL OR POSTNATAL INFANT INFECTIONS. LEVERAGING EXISTING LONGITUDINAL SAMPLES FROM 329 WLWH AND THEIR CHILDREN (COLLECTED DURING PREGNANCY, AT DELIVERY, AND UNTIL 6 WEEKS POSTPARTUM), WE WILL ADDRESS THE FOLLOWING SPECIFIC AIMS: 1) ESTIMATE THE FREQUENCY OF CMV REINFECTION DURING PREGNANCY AMONG WLWH USING NOVEL SEROLOGIC METHODS. 2) DETERMINE THE ASSOCIATION BETWEEN REINFECTION AND CMV REPLICATION OF SPECIFIC VIRAL STRAINS DURING PREGNANCY IN WLWH. 3) IDENTIFY GENOTYPIC FEATURES ASSOCIATED WITH TRANSMISSION TO PREGNANT WOMEN OR THEIR CHILDREN. SEROLOGICAL PROFILING WILL BE DONE USING TRADITIONAL CMV STRAIN-SPECIFIC ANTIBODIES AND NOVEL VIRSCAN TECHNOLOGY. VIRSCAN ALLOWS COMPREHENSIVE SEROLOGICAL PROFILING USING A PHAGE DISPLAY LIBRARY THAT WE HAVE ADAPTED TO BE ABLE TO IDENTIFY ALL ANTIBODIES TO ALL (>10,000) SEQUENCED CMV STRAINS/VARIANTS. CMV SHEDDING WILL BE DETERMINED BY QUANTITATIVE PCR ON MATERNAL & INFANT SALIVA AND MATERNAL BLOOD & VAGINAL SWABS. CMV GENOMIC ANALYSES WILL BE CONDUCTED ON PCR POSITIVE SAMPLES USING NEXT-GENERATION SEQUENCING TECHNIQUES COMBINED WITH MACHINE LEARNING. THE STRAINS PRESENT IN PREGNANT WOMEN WILL BE CHARACTERIZED AND THOSE TRANSMITTED TO INFANTS WILL BE SEQUENCED. SINGLE NUCLEOTIDE POLYMORPHISMS IN GENES THAT DISTINGUISH TRANSMITTED FROM NON-TRANSMITTED VIRUSES WITH POTENTIAL FUNCTIONAL SIGNIFICANCE WILL BE IDENTIFIED. STATISTICAL ANALYSES WILL EVALUATE ASSOCIATIONS BETWEEN CMV/HIV PARAMETERS AND OUTCOMES OF INTEREST INCLUDING MATERNAL REINFECTION AND CONGENITAL/POSTNATAL INFECTION. THE KNOWLEDGE GAINED FROM THIS PROJECT MAY RESULT IN PREVENTATIVE RECOMMENDATIONS FOR MATERNAL REINFECTIONS BASED ON NEWLY ELUCIDATED RISK FACTORS SPECIFIC TO WLWH, TREATMENT FOR REINFECTION DURING PREGNANCY, AND PREVENTION OF CONGENITAL INFECTION. FINALLY, THIS MAY HELP TO REDUCE THE ENORMOUS BURDEN OF CMV INFECTION ON FAMILIES AFFECTED BY HIV, BY INFORMING WHICH CMV GENOTYPES RESULT IN CMV TRANSMISSION AND SHOULD THEREFORE BE INCLUDED IN CANDIDATE VACCINES.